Colorectal liver metastases are more often super wild type. Toward treatment based on metastatic site genotyping?

Recent data showed that metastatic colorectal (mCRC) tumors exhibiting extended RAS-BRAF mutations were resistant to anti-epidermal growth factor receptor (EGFR) monoclonal antibodies, making these drugs suitable for the so-called "super" wild-type (WT) patients only. This study aimed to compare the extended RAS-BRAF mutation frequency and characteristics according to location of tumor sampling. All consecutive mCRC specimens (N = 1659) referred to our institution from January 2008 till June 2014 were included in the analysis. Tumor genotyping (first for KRAS exon 2, then for BRAF exon 15, and later for KRAS exons 2, 3, and 4 and NRAS exons 2, 3, and 4) was performed with high-resolution melting analysis or allelic discrimination. The factors predicting for the presence of mutation were explored using multivariate binary logistic regression. Overall, the prevalence of KRAS exon 2 was 36.8%, and it was lower in liver metastases (N = 138/490; 28.2%) in comparison with primary tumors (N = 442/1086; 40.7%), lung metastases (16/32; 50%), or other metastatic sites (15/51; 29.4%; P < 0.0001). Similarly, in the 1428 samples analyzed, BRAF mutations were less often found in liver metastases (N = 9/396; 2.3%) as compared to primary tumors (N = 79/959; 8.2%), lung metastases (N = 2/29; 6.9%), or other metastatic locations (N = 2/44; 4.5%; P < 0.0002). Overall occurrence of extended RAS mutation was 51.7%. Of the 503 samples tested, the prevalence of extended RAS-BRAF mutations was twice as low in liver metastases (N = 53/151; 34.2 %) as compared to primary tumors (N = 191/322; 59.3%, P < 0.0001). Univariate analysis identified age ≤65 years, male gender, and liver localization as predictors of super WT status. At multivariate analysis, only liver metastases were retained (RR 2.85 [95% CI 1.91-4.30]). Colorectal liver metastases are twice as likely to exhibit a super WT genotype as compared to other tumor locations independently from other factors. This molecular feature has the potential to influence therapeutic strategy in mCRC patients.

A safety analysis of oral prednisone as a pretreatment for rituximab in rheumatoid arthritis.

The administration of 100 mg of methylprednisolone intravenously (IV) 1/2 h prior to rituximab decreases the incidence of acute infusion reactions (AIRs). However, this pretreatment adds considerable time and conveys potential risk. We performed an open-label prospective assessment of oral prednisone as a pretreatment to rituximab. This was a 26-week open-label trial of 40 mg of oral prednisone given 1/2 h prior to rituximab as a prophylaxis against AIRs in patients with rheumatoid arthritis (RA). The primary endpoint was AIRs in the first 24 h after their initial infusion. Secondary endpoints include AIRs during the 24 h following their second infusion and any adverse events experienced during the 26-week study; efficacy measures were also followed as secondary endpoints. Sixty-four subjects were screened, and 50 subjects qualified. Fourteen out of the 50 (28 %) subjects had AIRs within 24 h of their first infusion. There were four AIRs (8.3 %) within 24 h of their second infusion. One of day 0 AIRs required drug discontinuation (wheezing/bronchospasm). Forty out of 50 (80 %) subjects experienced an adverse event during the 26 weeks. There were three SAEs deemed not to be study-drug related. The DAS28 and HAQ-DI all improved significantly at weeks 8, 16, and 26 compared to baseline. Historical controls demonstrate that 27 % of RA subjects experience AIRs with their first rituximab infusion. Our data suggest a smaller dose of oral prednisone is an effective alternative to IV methylprednisolone as a pretreatment for rituximab in patients with RA.

Operative risks of domino liver transplantation for the familial amyloid polyneuropathy liver donor and recipient: a double analysis.

Although domino liver transplantation (LT) is an established procedure, data about the operative risks are limited. This study aimed at evaluating the operative risks of domino LT. Two retrospective analyses were conducted (comparison of familial amyloid polyneuropathy [FAP] liver donors [61 patients] vs. FAP nondonors [39 patients] and FAP liver recipients [61 patients] vs. deceased donor liver recipients [61 patients]). First analysis showed a 60-day mortality of 6.6% for FAP donors and 7.7% for FAP nondonors (p = 1.0). No patient developed primary graft nonfunction. Acute rejection was higher in FAP nondonors compared to FAP donors (38.5% vs. 13.1%). Both groups had similar vascular and biliary complication rates. ICU stay was similar, whereas total hospitalization was longer for FAP nondonors. Both groups had similar 1- and 5-year patient and graft survival rates (83.4% vs. 87.2%, and 79.8% vs. 71.8%, p = 0.7) and (83.3% vs. 87.2%, and 79.1% vs.71.8%, p = 0.7). The second analysis showed a 1.6% mortality for FAP liver recipients vs. 3.2% of the control group (p = 1). Both groups had similar morbidity and technical complication rates (18.0% vs. 13.1%, p = 0.45) and (0.18 vs. 0.15, p = 0.65). The domino procedure does not add any risk to FAP donor or recipient. It increases the organ pool allowing transplantation of marginal recipients who otherwise are denied deceased donor liver transplantation.

Combination antibiotics as a treatment for chronic Chlamydia-induced reactive arthritis: a double-blind, placebo-controlled, prospective trial.

OBJECTIVE: Chlamydia trachomatis and Chlamydophila (Chlamydia) pneumoniae are known triggers of reactive arthritis (ReA) and exist in a persistent metabolically active infection state in the synovium, suggesting that they may be susceptible to antimicrobial agents. The goal of this study was to investigate whether a 6-month course of combination antibiotics is an effective treatment for patients with chronic Chlamydia-induced ReA. METHODS: This study was a 9-month, prospective, double-blind, triple-placebo trial assessing a 6-month course of combination antibiotics as a treatment for Chlamydia-induced ReA. Eligible patients had to be positive for C trachomatis or C pneumoniae by polymerase chain reaction (PCR). Groups received 1) doxycycline and rifampin plus placebo instead of azithromycin; 2) azithromycin and rifampin plus placebo instead of doxycycline; or 3) placebos instead of azithromycin, doxycycline, and rifampin. The primary end point was the number of patients who improved by 20% or more in at least 4 of 6 variables without worsening in any 1 variable in both combination antibiotic groups combined and in the placebo group at month 6 compared with baseline. RESULTS: The primary end point was achieved in 17 of 27 patients (63%) receiving combination antibiotics and in 3 of 15 patients (20%) receiving placebo. Secondary efficacy end points showed similar results. Six of 27 patients (22%) randomized to combination antibiotics believed that their disease went into complete remission during the trial, whereas no patient in the placebo arm achieved remission. Significantly more patients in the active treatment group became negative for C trachomatis or C pneumoniae by PCR at month 6. Adverse events were mild, with no significant differences between the groups. CONCLUSION: These data suggest that a 6-month course of combination antibiotics is an effective treatment for chronic Chlamydia-induced ReA.

Adjuvant effect of LPS and killed Propionibacterium acnes on the development of experimental gastrointestinal nematode infestation in sheep.

Gastrointestinal helminthic infection is an important worldwide sheep disease. The emergence of anthelminthic resistance has led to drives to seek new means of therapeutic control of helminthiasis in sheep. Several data demonstrated the adjuvant effect of Propionibacterium acnes on resistance to infection. Herein, we evaluate the adjuvant effect of the commercial suspension containing LPS and P. acnes on experimental helminthiasis. Sheep received three doses of LPS and P. acnes commercial suspension or saline 0.9% (control group). Both groups received orally Haemonchus contortus infective larvae on day 0. Parasitological, haematological, lymphoproliferation analysis, IL-5 and IgE determination were made once a week until 35th day after infection. Our results revealed increase on packed cell volumes on day 14, in LPS + P. acnes treated group. On 21st and 35th days after infection in the same group occurred increase on circulating eosinophils and lymphocytes, and also in the lymphoproliferative response to mitogen. On 35th day, the faecal eggs peak in LPS + P. acnes treated group was significantly lower than control. A negative correlation between faecal eggs counts and circulating eosinophils in the immunostimulant treated group was also observed. Our findings suggest that LPS + P. acnes suspension can be used as a strategy to control helminthiasis in sheep.

[Intestinal endometriosis. Three new cases and review of the literature]. / Endometriosi intestinale. Tre nuovi casi e revisione della Letteratura.

OBJECTIVE: The study was undertaken to identify some features of the intestinal endometriosis such as symptoms, helpful investigations, pattern of distribution and surgical management. PATIENTS: Three consecutive cases, observed during a sixteen month period, are reported. The most frequent symptoms were chronic pelvic and abdominal pain, dysmenorrhea, alterated bowel habit and menorrhagia. The diagnosis of intestinal endometriosis was incidental in all but one case admitted for an intestinal subocclusive syndrome in patient with a past history of pelvic endometriosis previously documented by laparoscopy. RESULTS: All patients presented a sigmoid localization of endometriosis with different degree of stenosis and underwent sigmoid resection, followed by a resolution of abdominal symptoms. DISCUSSION: Although the exact frequency of intestinal endometriosis is difficult to know because of the lack of specific symptoms and reliable investigations, it has been estimated that implants to the bowel may occur in 3%-37% of women affected by endometriosis. The sigmoid colon is the most common site of localization. The main symptoms are pelvic pain, dysmenorrhea, infertility and diarrhoea or constipation; rarely patients present bowel occlusion due to stenosis (less than 15% of the cases) or cyclic rectal bleeding. CONCLUSION: Generally, intestinal endometriosis is not suspected preoperatively in those patients without a past history of this condition; however an accurate diagnosis can be provided throughout laparoscopy, before open surgery. The hormonal therapy is not successful in alleviating moderate to severe obstructive symptoms. Thus surgery still remains the most effective treatment for advanced intestinal endometriosis.